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Modafinil - Excitotoxicity

Reminisant B

Reminisant B

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Nov 3, 2005
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http://en.wikipedia.org/wiki/Excitotoxicity

Modafinil & similar drugs work by indirectly increasing glutamate as well as potentially other mechanisms [?]

There seems to be no evidence (so far) that modafinil causes damage and some studies have shown a protective effect.

I'm not trying to do a ricaurte and cause unfounded panic but does anyone have any views of whether such drugs may be causing unseen cumulative damage which may only show up years in the future?

Like I say there is no evidence to suggest it does, it just seems a potential risk as soon as you bring increased levels of glutamate in the equation. [?] I have possibly overlooked something - glutamate is one complicated topic.
 
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Modafinil prevents glutamate cytotoxicity in cultured cortical neurons.

Antonelli T, Ferraro L, Hillion J, Tomasini MC, Rambert FA, Fuxe K
Department of Experimental and Clinical Medicine, University of Ferrara, Italy.


The ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08 ). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons.
Click to expand...

Possibly attenuation of glutamate is a good thing [?]. I.e not crudely increasing levels [as would happen if your BBB failed] but modulating it's effects.

Still seems a potential concern that damaging effects might not show up till a long time in the future [?] Reye's Syndrome was only found 100years after aspirin's discovery.
 
Reminisant B said:
Possibly attenuation of glutamate is a good thing [?]. I.e not crudely increasing levels [as would happen if your BBB failed] but modulating it's effects.

Still seems a potential concern that damaging effects might not show up till a long time in the future [?] Reye's Syndrome was only found 100years after aspirin's discovery.
Click to expand...
I don't have 100 years to wait to find out whether modafinil is subject to excitotoxicity, and develop some accelerated form of prion caused degeneration.
From a recent article, I found that they claimed the mechanisms responsible for modafinil's effects were due to the catecholaminergic NT signaling, rather than what another 2002 study claimed to be the opposite. Attributing primary effects to 5-HT and GABAergic systems.
With regard to the more recent article, wouldn't modafinil's role in increasing extracellular glutamate heighten incidence of excitoxicity despite a lack of evidence?
 
There is some interesting research on this subject here: http://www.dtic.mil/dtic/tr/fulltext/u2/p011050.pdf
I would imagine that prolonged dosing would indeed result in upregulation and in turn rebound excitotoxicity, however this reminds me of how DXM has metabolites specifically 3-hydroxymorphinan that help mediate the parent compounds toxicity. Perhaps modafinil has a similar metabolic dampening effect, however this is just conjecture at this point.
 
Serotonergic psychedelics strongly enhance glutamatergic neurotransmission and aren't associated with any neurotoxicity.

I can't think of a more benign psychoactive drug than Modafinil. It has literally no side effects (other than changing the smell of my urine).
 
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